Melanin-The Éminence Grise of Melanoma and Parkinson's Disease Development

Abstract

A common feature of Parkinson's disease (PD) and melanoma is their starting points being based on cells capable of converting tyrosine into melanin. Melanocytes produce two types of melanin: eumelanin and pheomelanin. These dyes are designed to protect epidermal cells from the harmful effects of UV radiation. Neurones of the substantia nigra, which degenerate during PD, produce neuromelanin, the physiological role of which is not fully explained. This article discusses the potential role of melanins in the pathogenesis of both diseases. Melanins, due to their ability to accumulate toxic substances, may become their sources over time. The use of glutathione for the synthesis of pheomelanins and neuromelanins may reduce the antioxidant capacity of cells, leading to an excessive synthesis of free radicals. This study also tested the hypothesis that certain drugs used in the treatment of PD (L-DOPA, MAO-B and COMT inhibitors, and amantadine), aimed at increasing dopamine concentration, could potentially contribute to the development of melanoma. The role and properties of melanins should continue to be researched. Whether excessive melanin synthesis or its accumulation in the extracellular space may be factors initiating the development of diseases remains an open question.

Keywords: Parkinson’s disease; dopamine; eumelanin; melanoma; neuromelanin; pheomelanin.

Figure 1

Simplified scheme of melanin synthesis. Tyrosine is a precursor to DOPA and Dopaquinone (DOPAQ). In dopamine-producing cells, there is a partially spontaneous conversion of dopamine to 5,6-dihydroxyindole (DHI), which can also be formed directly from Dopachrome (DOPAC). The synthesis of neuromelanin and pheomelanin requires glutathione. (5SCD) 5-S-cysteinyldopa, (5SCDA)5-S-cysteinyldopamine. Dashed line arrows represent several reactions. The letter “S” in a circle represents the sulfur of the thiol group. Based on [16,17].

Figure 2

Proposed mechanism for the role of eumelanin and pheomelanin in the development of melanoma. The amount of melanin increases under the influence of UV radiation. Melanins have protective properties against UV rays, but the reduction of the glutathione level used for the synthesis of pheomelanin can induce oxidative stress [25]. In addition, melanins accumulate metal ions and toxins, which, when released gradually (red arrows), can potentially increase oxidative stress [29]. Certainly, this is not the only factor determining the development of melanoma.

Figure 3

Proposed mechanism of neurodegeneration of neuromelanin-producing cells. During life, the amount of intracellular and extracellular neuromelanin increases, protecting cells from damage. After a certain threshold, accumulated toxins and metal atoms can be released (red arrows), leading to increased oxidative stress and cell degeneration. The mechanism that triggers the cascade of biochemical processes leading to neurodegeneration is unknown. Based on [38,42].

Figure 4

Scheme of action of L-DOPA, amantadine, rasagiline and entacapone leading to an increase in DA concentration in the synaptic space. In the presynaptic neurone, tyrosine is converted to L-DOPA and then to DA, which is placed in the synaptic vesicles waiting for a signal to be released outside the cell. In the synaptic space, DA binds to receptors in the membrane of the postsynaptic neurone, transmitting the impulse. L-DOPA is a direct precursor of DA, increasing its concentration in the brain. Amantadine increases DA secretion outside the cell. Rasagiline inhibits the breakdown of DA to homovanillic acid (HVA) by monoamine oxidase type B (MAOB), and entacapone inhibits the breakdown of DA by catechol-O-methyltransferase (COMT).